Clinical Care/Education/Nutrition/Psychosocial Research
B R I E F
R E P O R T
Pleiotropic Action of Short-Term Metformin
and Fenofibrate Treatment, Combined
With Lifestyle Intervention, in Type 2
Diabetic Patients With Mixed Dyslipidemia
MACIEJ PRUSKI, MD
ROBERT KRYSIAK, MD
BOGUSLAW OKOPIEN, MD, PHD
OBJECTIVE — To compare the effect of short-term metformin and fenofibrate treatment,
administered alone or in sequence, on glucose and lipid metabolism, cardiovascular risk factors,
and monocyte cytokine release in type 2 diabetic patients with mixed dyslipidemia.
RESEARCH DESIGN AND METHODS — We studied 128 type 2 diabetic patients with
mixed dyslipidemia complying throughout the study with lifestyle intervention who were randomized twice, initially to either metformin or placebo, and then to micronized fenofibrate or
placebo.
RESULTS — Fenofibrate alleviated diabetic dyslipidemia–induced changes in plasma highsensitivity C-reactive protein, fibrinogen, and plasminogen activator inhibitor (PAI)-1 and in
monocyte cytokine release, whereas metformin or lifestyle intervention improved mainly glucose and lipid metabolism. The strongest pleiotropic effect was observed when fenofibrate was
added to metformin.
CONCLUSIONS — Fenofibrate, particularly administered together with metformin, is superior to metformin and lifestyle intervention in exhibiting beneficial effects on systemic inflammation, hemostasis, and monocyte secretory function in type 2 diabetic patients with mixed
dyslipidemia.
Diabetes Care 32:1421–1424, 2009
P
eroxisome proliferator–activated receptor (PPAR)-␣ activators (fibrates) administered to patients
with dyslipidemia (1– 4) or early glucose
metabolism abnormalities (5) produce
many non–lipid-related effects, including
anti-inflammatory, antioxidant, and antithrombotic actions and improvement in
endothelial function. Apart from normalizing glucose metabolism, metformin, the
only oral antidiabetic medication shown
to decrease cardiovascular events independent of glycemic control (6), improved dyslipidemia, hemostasis, and
systemic inflammation (7). To the best of
our knowledge, no previous clinical study
has ever compared clinical benefits of
metformin and fibrates when it comes to
their pleiotropic effects and assessed
whether metformin-fibrate combination
is superior to treatment with only one of
these drugs.
RESEARCH DESIGN AND
METHODS — The patients included
in the study met the following criteria: 1)
recently diagnosed and previously untreated type 2 diabetes (fasting plasma
glucose at least 126 mg/dl or plasma glucose concentration 2 h after a glucose load
at least 200 mg/dl) and 2) mixed dyslipidemia (plasma total cholesterol ⬎200
mg/dl, LDL cholesterol ⬎130 mg/dl, triglycerides ⬎150 mg/dl). The exclusion
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
From the Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland.
Corresponding author: Robert Krysiak, r.krysiak@interia.pl.
Received 30 December 2008 and accepted 27 April 2009.
Published ahead of print at http://care.diabetesjournals.org on 12 May 2009. DOI: 10.2337/dc08-2335.
© 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.
org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby
marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
DIABETES CARE, VOLUME 32, NUMBER 8, AUGUST 2009
criteria are presented in the supplemental
data, available in an online appendix at
http://care.diabetesjournals.org/cgi/content/
full/dc08-2335/DC1. The study protocol
was approved by the local ethics committee.
All included patients (n ⫽ 128) were given
detailed advice about how to achieve the
goals of lifestyle modification, which were a
reduction in weight of 7% or more if necessary, total fat intake ⬍30% of total energy
intake, saturated fat intake ⬍7% of energy
consumed, cholesterol intake ⬍200 mg/
day, an increase in fiber intake to 15 g per
1,000 kcal, and moderate to vigorous exercise for at least 30 min/day. The patients
were randomized in a double-blind fashion
to metformin (850 mg; n ⫽ 66) or placebo
(n ⫽ 62), which were administered twice
daily for 60 days. After 30 days of treatment,
patients of each group were again randomized to receive once daily at bedtime either
micronized fenofibrate (267 mg daily) or
placebo, and the treatment with metformin ⫹ fenofibrate (n ⫽ 33), metformin ⫹
placebo (n ⫽ 33), placebo ⫹ fenofibrate
(n ⫽ 31), or placebo ⫹ placebo (n ⫽ 31)
together with lifestyle intervention were
continued for the following 30 days. All
treatment groups were compared with two
age-, sex-, and weight-matched groups of
patients: type 2 diabetic subjects with
mixed dyslipidemia (n ⫽ 32) and control
normoglycemic and normolipidemic subjects (n ⫽ 32). Patients belonging to both of
these groups were briefly informed about
the benefits of a healthy diet but were not
prescribed any special dietary and exercise
recommendations. Lipid profile, plasma
glucose, insulin, high-sensitivity C-reactive
protein (hsCRP), fibrinogen, plasminogen
activator inhibitor (PAI)-1, homeostasis assessment (HOMA) index, A1C, and monocyte release of tumor necrosis factor
(TNF)-␣ and interleukin-1␤ were determined before and after 30 and 60 days of
therapy (3,5). Statistical analysis was performed as previously described (3,5).
RESULTS — At baseline, there was no
difference between the groups in terms of
sex, weight, age, medical background,
and clinical characteristics. Apart from
1421
Pleiotropic action of metformin and fenofibrate treatment
Table 1—Effect of metformin and fenofibrate, administered alone or in sequence, together with lifestyle intervention on lipid profile, glucose
metabolism, low-grade inflammation, hemostasis, and cytokine secretion by stimulated monocytes in type 2 diabetic patients with mixed
dyslipidemia
Type 2 diabetic patients with mixed dyslipidemia complying with lifestyle intervention
Placebo ⫹ placebo Metformin ⫹ placebo
Placebo ⫹
fenofibrate
Metformin ⫹
fenofibrate
Patients not complying with
lifestyle intervention
Diabetic
dyslipidemia㛳
Number of
30
31
30
33
32
patients
Fasting glucose
(mg/dl)
Baseline
169.1 ⫾ 4.4***
168.8 ⫾ 4.1***
164.5 ⫾ 3.1***
165.9 ⫾ 3.2***
165.8 ⫾ 4.6***
After 30 days 141.0 ⫾ 5.6***†† 121.8 ⫾ 4.9***††† 139.4 ⫾ 3.6***†
120.5 ⫾ 3.1***†††
162.2 ⫾ 4.0***
After 60 days 147.5 ⫾ 3.9***†
109.6 ⫾ 4.3***†††‡ 142.1 ⫾ 3.2***†
106.1 ⫾ 3.7*†††‡
167.2 ⫾ 3.8***
HOMA
Baseline
11.5 ⫾ 0.7***
11.7 ⫾ 0.6***
11.3 ⫾ 0.8***
11.9 ⫾ 0.7***
11.4 ⫾ 0.8***
After 30 days
11.1 ⫾ 0.6***
8.0 ⫾ 0.6***†
10.9 ⫾ 0.5***
8.9 ⫾ 0.8***†
11.6 ⫾ 0.6***
After 60 days
10.3 ⫾ 0.5***†
6.8 ⫾ 0.4***†††
8.7 ⫾ 0.6***††‡
5.0 ⫾ 0.4**†††‡‡‡
11.3 ⫾ 0.9***
A1C (%)
Baseline
7.5 ⫾ 0.2***
7.4 ⫾ 0.2***
7.5 ⫾ 0.2***
7.4 ⫾ 0.1***
7.4 ⫾ 0.3***
After 30 days
7.0 ⫾ 0.2***†
6.5 ⫾ 0.2***††
7.0 ⫾ 0.2***†
6.5 ⫾ 0.2***††
7.4 ⫾ 0.2***
After 60 days
7.0 ⫾ 0.2***†
6.2 ⫾ 0.1***†††
6.7 ⫾ 0.2***††
6.1 ⫾ 0.1**†††
7.3 ⫾ 0.2***
Total cholesterol
(mg/dl)
Baseline
226.5 ⫾ 4.1***
229.3 ⫾ 3.2***
228.1 ⫾ 4.2***
232.1 ⫾ 3.6***
228.8 ⫾ 5.4***
After 30 days 224.4 ⫾ 4.2***
228.3 ⫾ 2.5***
216.6 ⫾ 3.2***
221.1 ⫾ 3.5***
230.1 ⫾ 3.4***
After 60 days 229.3 ⫾ 5.0***
223.6 ⫾ 4.0***
188.3* ⫾ 4.5**††‡
183.8 ⫾ 4.0*†††‡‡
231.1 ⫾ 2.3***
LDL cholesterol
(mg/dl)
Baseline
148.2 ⫾ 2.3***
150.3 ⫾ 2.6***
149.0 ⫾ 3.2***
150.6 ⫾ 2.6***
151.1 ⫾ 3.5***
After 30 days 148.1 ⫾ 2.4***
147.0 ⫾ 3.1***
139.8 ⫾ 4.1***
142.2 ⫾ 2.0***
147.4 ⫾ 2.8***
After 60 days 145.0 ⫾ 3.0***
140.9 ⫾ 3.5***
115.1 ⫾ 3.2†††‡
113.4 ⫾ 1.9†††‡‡
145.4 ⫾ 3.7***
HDL cholesterol
(mg/dl)
Baseline
40.1 ⫾ 1.0***
39.5 ⫾ 1.1***
40.4 ⫾ 1.1***
39.2 ⫾ 1.0***
39.9 ⫾ 1.1***
After 30 days
41.8 ⫾ 0.7***
40.1 ⫾ 0.3***
40.6 ⫾ 0.6***
41.5 ⫾ 0.4**
39.0 ⫾ 1.3***
After 60 days
42.1 ⫾ 0.6***
41.0 ⫾ 0.3***
43.2 ⫾ 0.5**††
43.7 ⫾ 0.3*††
39.2 ⫾ 0.6***
Triglycerides
(mg/dl)
Baseline
206.8 ⫾ 6.4***
219.6 ⫾ 5.2***
214.8 ⫾ 6.8***
215.9 ⫾ 5.5***
214.4 ⫾ 8.8***
After 30 days 193.8 ⫾ 6.8***
198.6 ⫾ 5.1***
204.8 ⫾ 5.3***
190.6 ⫾ 4.5***
212.5 ⫾ 8.0***
After 60 days 181.5 ⫾ 8.2***†
184.5 ⫾ 6.0***†
166.8 ⫾ 7.8**†††
142.2 ⫾ 8.2†††
210.0 ⫾ 7.8***
hsCRP (mg/l)
Baseline
3.0 ⫾ 0.2***
2.9 ⫾ 0.2***
2.8 ⫾ 0.2***
2.9 ⫾ 0.2***
2.8 ⫾ 0.1***
After 30 days
2.8 ⫾ 0.3***
2.5 ⫾ 0.2***
2.5 ⫾ 0.2***
2.7 ⫾ 0.2***
2.8 ⫾ 0.2***
After 60 days
2.8 ⫾ 0.3***
2.2 ⫾ 0.1***†
1.9 ⫾ 0.4***†
2.0 ⫾ 0.2***††‡
2.7 ⫾ 0.2***
Fibrinogen (mg/
dl)
Baseline
455.0 ⫾ 48.1***
474.1 ⫾ 32.9***
453.5 ⫾ 37.6***
469.9 ⫾ 18.3***
474.2 ⫾ 32.1***
After 30 days 467.8 ⫾ 45.1***
440.2 ⫾ 49.0***
465.1 ⫾ 35.4***
443.1 ⫾ 54.2***
486.0 ⫾ 21.0***
After 60 days 460.5 ⫾ 51.6***
436.4 ⫾ 29.5***
391.2 ⫾ 36.7***†‡ 346.3 ⫾ 48.9*††‡
475.1 ⫾ 27.5***
PAI-1 (ng/ml)
Baseline
101.5 ⫾ 4.1***
99.4 ⫾ 3.9***
102.0 ⫾ 4.8***
95.7 ⫾ 3.6***
101.1 ⫾ 5.2***
After 30 days 100.6 ⫾ 6.1***
94.8 ⫾ 3.8***
94.8 ⫾ 5.1***
92.0 ⫾ 2.7***
102.4 ⫾ 4.4***
After 60 days 103.3 ⫾ 5.7***
92.1 ⫾ 4.0***
73.9 ⫾ 4.6***††‡
69.8 ⫾ 4.5**†††‡
100.8 ⫾ 4.6***
TNF-␣ release
(pg/ml)
Baseline
1,530.0 ⫾ 68.1*** 1,453.5 ⫾ 42.1*** 1,511.2 ⫾ 64.5*** 1,449.8 ⫾ 53.2***
1,489.1 ⫾ 71.1***
1422
Control
subjects¶
32
90.1 ⫾ 2.2
90.5 ⫾ 2.0
88.2 ⫾ 1.9
2.1 ⫾ 0.2
2.0 ⫾ 0.1
2.2 ⫾ 0.2
5.1 ⫾ 0.2
5.0 ⫾ 0.1
5.1 ⫾ 0.2
162.0 ⫾ 4.2
160.0 ⫾ 3.2
159.9 ⫾ 2.3
108.1 ⫾ 2.8
110.4 ⫾ 2.6
110.7 ⫾ 2.7
47.8 ⫾ 0.7
48.0 ⫾ 0.6
47.1 ⫾ 0.5
122.4 ⫾ 3.2
121.1 ⫾ 4.0
120.4 ⫾ 4.6
1.0 ⫾ 0.1
1.0 ⫾ 0.2
1.1 ⫾ 0.1
296.5 ⫾ 22.0
285.1 ⫾ 23.4
290.3 ⫾ 19.8
49.6 ⫾ 6.2
48.1 ⫾ 4.2
48.9 ⫾ 5.1
901.7 ⫾ 46.6
DIABETES CARE, VOLUME 32, NUMBER 8, AUGUST 2009
Pruski, Krysiak, and Okopien
Table 1—Continued
Type 2 diabetic patients with mixed dyslipidemia complying with lifestyle intervention
Placebo ⫹ placebo Metformin ⫹ placebo
After 30 days 1,486.6 ⫾ 70.8***
After 60 days 1,484.2 ⫾ 56.7***
Interleukin-1␤
release
(pg/ml)
Baseline
132.5 ⫾ 5.2***
After 30 days
146.8 ⫾ 7.3***
After 60 days
145.2 ⫾ 3.8***
1,382.4 ⫾ 35.1***
1,108.9 ⫾ 52.0**†
136.3 ⫾ 6.8***
139.0 ⫾ 5.9***
126.8 ⫾ 7.3***
Placebo ⫹
fenofibrate
1,332.4 ⫾ 53.2**
830.1 ⫾ 69.0††
136.5 ⫾ 7.0***
125.8 ⫾ 8.0**
90.3 ⫾ 5.6†††‡‡
Metformin ⫹
fenofibrate
Patients not complying with
lifestyle intervention
Diabetic
dyslipidemia㛳
Control
subjects¶
1,028.9 ⫾ 87.3*†
1,523.1 ⫾ 68.2*** 895.3 ⫾ 38.2
620.1 ⫾ 35.9†††‡‡ 1,510.8 ⫾ 36.4*** 908.2 ⫾ 44.5
138.8 ⫾ 7.1***
139.5 ⫾ 6.4***
92.5 ⫾ 7.0†††‡‡
135.0 ⫾ 4.0***
138.4 ⫾ 3.9***
130.1 ⫾ 6.8***
86.1 ⫾ 6.5
90.2 ⫾ 5.4
87.5 ⫾ 3.2
Data are means ⫾ SEM. *P ⬍ 0.05, **P ⬍ 0.01, ***P ⬍ 0.001 vs. control subjects; †P ⬍ 0.05, ††P ⬍ 0.01, †††P ⬍ 0.001 vs. baseline values, ‡P ⬍ 0.05, ‡‡P ⬍
0.01, ‡‡‡P ⬍ 0.001 vs. values after 30 days of treatment. 㛳Type 2 diabetic patients with mixed dyslipidemia. ¶Subjects without carbohydrate and lipid abnormalities.
differences in lipid profile and glucose
metabolism markers, the presence of diabetes and dyslipidemia was associated
with higher plasma levels of hsCRP, fibrinogen, and PAI-1 and the increased
release of both cytokines (see the supplemental Table, available in the online appendix). No serious adverse effects were
observed throughout the study, and 188
patients completed the study (see the supplemental Results, available in the online
appendix). Fenofibrate, administered
alone or added to metformin, alleviated
diabetic dyslipidemia–induced changes
in plasma hsCRP, fibrinogen, and PAI-1
and in monocyte cytokine release. In
turn, metformin or lifestyle intervention
improved mainly glucose and lipid metabolism (Table 1). Metformin ⫹ fenofibrate were superior to 1) placebo ⫹
placebo in affecting fasting glucose,
HOMA, A1C, total, LDL, and HDL cholesterol, triglycerides, hsCRP, fibrinogen,
PAI-1, and monocyte cytokine release; 2)
metformin ⫹ placebo in affecting HOMA,
total, LDL, and HDL cholesterol, triglycerides, fibrinogen, PAI-1, and cytokine
release; and 3) placebo ⫹ fenofibrate
group in affecting fasting glucose, HOMA,
A1C, triglycerides, fibrinogen, and
TNF-␣ release. Placebo ⫹ fenofibrate
were superior to 1) placebo ⫹ placebo in
reducing total and LDL cholesterol,
HOMA, hsCRP, fibrinogen, PAI-1,
TNF-␣, and interleukin-1␤ release; 2)
metformin ⫹ placebo group in reducing
total, LDL, and HDL cholesterol, fibrinogen and PAI-1, and monocyte release of
both cytokines; but 3) inferior to the latter
group in reducing plasma fasting glucose,
HOMA, and A1C. Metformin ⫹ placebo
were superior to placebo ⫹ placebo in
changing fasting glucose, HOMA, A1C,
DIABETES CARE, VOLUME 32, NUMBER 8, AUGUST 2009
and TNF-␣ release. At baseline, there was
a weak correlation between plasma
hsCRP and baseline cytokine release; between HOMA and plasma hsCRP, fibrinogen, and PAI-1; as well as well as
between HOMA and cytokine release (r
values between 0.42 and 0.51; P ⬍
0.001). Treatment-induced changes in
plasma hsCRP correlated weakly with the
changes in TNF-␣ and interleukin-1␤ release (r values from 0.45 to 0.59; P ⬍
0.001). No other correlations were found
in both baseline conditions and after
treatment (see the supplemental Results,
available in the online appendix).
CONCLUSIONS — This prospective
partially double-blind placebo-controlled
randomized study has shown that fenofibrate exhibited a stronger effect than
metformin and nonpharmacological intervention on systemic inflammation,
hemostasis, and monocyte secretory
function, disturbed by the presence of
type 2 diabetes and mixed dyslipidemia.
This multidirectional action of fenofibrate, which was lipid independent and
unrelated to the improvement in insulin
sensitivity, may contribute to the beneficial action of PPAR-␣ activators on the
reduction of cardiovascular events observed in some (8,9), but not other (10),
clinical trials. A weaker than anticipated
(11) action of metformin may be, at least
in part, explained by all treated subjects
complying with lifestyle modification, because placebo-treated patients following
the latter strategy were superior to not
complying patients in reducing plasma
glucose, HOMA, A1C, and triglycerides.
In our study, the treatment-induced
changes in glucose and lipid metabolism,
and in low-grade inflammation, hemosta-
sis, and monocyte cytokine release, were
strongest in patients treated with both of
these agents. Considering that the assessed markers are regarded as cardiovascular risk factors (12–14), the obtained
results suggest bringing by metforminfibrate combination some additional benefits to patients with diabetic dyslipidemia.
Taking into account that statins markedly
reduce cardiovascular risk and, if tolerated, should be given to all type 2 diabetic
patients (15), administration of metformin with fenofibrate may be considered an alternative treatment option in
subjects in whom statin therapy is either
contraindicated or results in adverse effects, including drug interactions.
Acknowledgments — The study was supported by grant number NN-1-70/06 of the
Medical University of Silesia.
No potential conflicts of interest relevant to
this article were reported.
We are indebted to Jaroslawa Sprada for her
excellent technical support.
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